End stage renal disease (ESRD) is associated with substantial morbidity and mortality. Strategies to prevent the renal function decline that can ultimately result in ESRD are essential. The impact of environmental exposures has received relatively little attention in this regard, despite the fact that exposures such as cadmium and lead are known renal toxicants that are stored long-term in the body and ubiquitous in humans. In fact, the lead and cadmium dose-effect curves for renal function remain uncertain for the low to moderate range of doses. The proposed study will investigate a broad set of causes of renal function decline, including lead, cadmium, blood pressure, diabetes, nephrotoxic medication use, genetic polymorphisms, and age. This application is a competing renewal application of the study "Exposure, dose, body burden, and health effects of lead" (Schwartz BS, PI) conducted from 1997-2001. It will build on data, from the large cohort of current and former lead workers and participants without occupational lead exposure in the originally funded grant. Study subjects have a wide range of lead exposure and dose measures and renal outcome data from three visits each over an average of 2.2 years. Analysis of existing data has already provided very important results, including longitudinal decline in renal function associated with lead dose measures; interaction between age and lead dose on renal function and renal function decline; interaction between ALAD genotype and lead dose on renal function; and associations of environmental level cadmium dose with elevated NAG in a subset of lead workers. However, in order to better understand the causes of renal function decline, cadmium dose must be characterized in all subjects, additional genotypes must be measured, and additional follow-up time is needed because of the slow rate of renal function decline. We propose to include 675 participants from the first study and enroll 225 new current or former lead workers over age 45 years, those at greater risk for renal function decline. We will obtain blood and tibia lead, genotyping, urinary cadmium, BUN, serum creatinine, measured and calculated creatinine clearances, NAG and RBP during 3 evaluations at yearly intervals. The specific aims are to determine: 1) if lead and cadmium dose are or continue to be associated with renal function at cross-section and longitudinally; 2) if there is effect modification by lead or cadmium dose, respectively, on associations between cadmium or lead dose and renal function decline; 3) if hypertension modifies the relations of lead or cadmium dose with renal function decline; and 4) whether polymorphisms in the genes for ALAD, VDR, ACE, and eNOS modify or continue to modify relations of lead and/or cadmium dose with renal outcomes. We believe the proposed work will allow a more complete understanding of the causes of renal function decline and lead to the development of public health interventions to prevent this considerable public health problem.